Ethynyl compounds useful for treatment of cns disorder

ABSTRACT

The present invention relates to ethynyl compounds of formula 
     
       
         
         
             
             
         
       
     
     wherein X, Y, Z, and R 4  are as defined herein
 
or to a pharmaceutically acceptable salt or acid addition salt, to a racemic mixture, or to its corresponding enantiomer and/or optical isomer and/or stereoisomer thereof. Compounds of formula I are positive allosteric modulators (PAM) of the metabotropic glutamate receptor subtype 5 (mGluR5) and they are therefore useful for the treatment of diseases related to this receptor.

PRIORITY TO RELATED APPLICATION(S)

This application claims the benefit of European Patent Application No.09179719.1, filed Dec. 17, 2009, which is hereby incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

Glutamate is the major excitatory neurotransmitter in the brain andplays a unique role in a variety of central nervous system (CNS)functions. The glutamate-dependent stimulus receptors are divided intotwo main groups. The first main group, namely the ionotropic receptors,forms ligand-controlled ion channels. The metabotropic glutamatereceptors (mGluR) belong to the second main group and, furthermore,belong to the family of G-protein coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. According to their sequence homology,signal transduction mechanisms and agonist selectivity, these eightreceptors can be sub-divided into three sub-groups:

mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to groupII and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the first groupcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, epilepsy, schizophrenia,Alzheimer's disease, cognitive disorders and memory deficits, Tuberoussclerosis as well as chronic and acute pain.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are ischemia, Huntington's chorea, amyotrophic lateralsclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy,idiopathic parkinsonism or parkinsonism caused by medicaments as well asconditions which lead to glutamate-deficiency functions, such as e.g.muscle spasms, convulsions, migraine, urinary incontinence, nicotineaddiction, opiate addiction, anxiety, vomiting, dyskinesia anddepressions.

Disorders mediated full or in part by mGluR5 are for example acute,traumatic and chronic degenerative processes of the nervous system, suchas Alzheimer's disease, senile dementia, Parkinson's disease,Huntington's chorea, amyotrophic lateral sclerosis and multiplesclerosis, psychiatric diseases such as schizophrenia and anxiety,depression, pain and drug dependency (Expert Opin. Ther. Patents (2002),12(12), 1845-1852 doi:10.1517/13543776.12.12.1845).

A new avenue for developing selective modulators is to identifycompounds which act through allosteric mechanism, modulating thereceptor by binding to a site different from the highly conservedorthosteric binding site. Positive allosteric modulators of mGluR5 haveemerged recently as novel pharmaceutical entities offering thisattractive alternative. Positive allosteric modulators have beendescribed, for example in WO2008/151184, WO2006/048771, WO2006/129199and WO2005/044797 and in Molecular Pharmacology (1991), 40, 333-336; TheJournal of Pharmacology and Experimental Therapeutics (2005) 313(1),199-206;

Positive allosteric modulators are compounds that do not directlyactivate receptors by themselves, but markedly potentiateagonist-stimulated responses, increase potency and maximum of efficacy.The binding of these compounds increases the affinity of aglutamate-site agonist at its extracellular N-terminal binding site.Positive allosteric modulation is thus an attractive mechanism forenhancing appropriate physiological receptor activation. There is ascarcity of selective positive allosteric modulators for the mGluR5receptor. Conventional mGluR5 receptor modulators typically lacksatisfactory aqueous solubility and exhibit poor oral bioavailability.Therefore, there remains a need for compounds that overcome thesedeficiencies and that effectively provide selective positive allostericmodulators for the mGluR5 receptor.

SUMMARY OF THE INVENTION

The present invention provides ethynyl compounds of formula I

wherein

-   X is N or C—R¹;-   Y is N or C—R²;-   Z is CH or N;-   R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2    nitrogen atoms, optionally substituted by 1 to 3 groups, selected    from halogen, lower alkyl, lower alkoxy and NRR′;-   R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower    hydroxyalkyl, lower cycloalkyl or heterocycloalkyl optionally    substituted with hydroxy or alkoxy;-   R² is hydrogen, CN, lower alkyl or heterocycloalkyl;-   R and R′ are each independently hydrogen or lower alkyl;    or a pharmaceutically acceptable salt or acid addition salt, a    racemic mixture, corresponding enantiomer and/or optical isomer,    and/or stereoisomer thereof.

Compounds of formula I are distinguished by having valuable therapeuticproperties. They are positive allosteric modulators (PAM) of themetabotropic glutamate receptor subtype 5 (mGluR5). They can be used inthe treatment or prevention of disorders, relating to positiveallosteric modulators for the mGluR5 receptor. The most preferredindications for compounds which are positive allosteric modulators areschizophrenia and cognition.

The present invention relates to compounds of formula I and to theirpharmaceutically acceptable salts and pharmaceutical compositionscontaining them. The invention also provides processes for theirproduction as well as to their use in the treatment or prevention ofdisorders, relating to positive allosteric modulators for the mGluR5receptor, such as schizophrenia and cognition and to pharmaceuticalcompositions containing the compounds of formula I.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of the general terms used in the presentdescription apply irrespective of whether the terms in question appearalone or in combination.

As used herein, the term “halogen” denotes chlorine, bromine, iodine,and fluorine.

As used herein, the term “lower alkyl” denotes a saturated, i.e.aliphatic hydrocarbon group including a straight or branched carbonchain with 1-4 carbon atoms. Examples for “alkyl” are methyl, ethyl,n-propyl, isopropyl and tert-butyl.

The term “alkoxy” denotes a group —O—R′ wherein R′ is lower alkyl asdefined above.

The term “ethynyl” denotes the group —C≡C—.

The term “lower hydroxyalkyl” denotes a lower alkyl groups as definedabove, wherein at least one hydrogen atom is replaced by hydroxy.

The term “lower cycloalkyl” denotes a saturated carbon ring, containingfrom 3 to 7 carbon ring atoms, for example cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or cycloheptyl.

The term “heterocycloalkyl” denotes a saturated carbon ring, containingone or more oxygen or nitrogen atoms, a preferred heteroatom is O.Examples for such rings are tetrahydropyran-2, 3 or 4-yl, pyrrolidinyl,imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl or morpholinyl.

The term “6-membered aromatic substituent containing 0, 1 or 2 nitrogenatoms” includes, but not limited to, the following aromatic rings:phenyl, 2,3- or 4-pyridinyl or pyrimidinyl.

“Pharmaceutically acceptable,” such as pharmaceutically acceptablecarrier, excipient, etc., means pharmacologically acceptable andsubstantially non-toxic to the subject to which the particular compoundis administered.

The term “pharmaceutically acceptable salt” or “pharmaceuticallyacceptable acid addition salt” embraces salts with inorganic and organicacids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoricacid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid,succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonicacid and the like.

“Therapeutically effective amount” means an amount that is effective toprevent, alleviate or ameliorate symptoms of disease or prolong thesurvival of the subject being treated.

In one embodiment, the invention provides compounds of formula I,wherein X is C—R¹ and Y is C—R² and Z is N,

wherein

-   R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2    nitrogen atoms, optionally substituted by 1 to 3 groups, selected    from halogen, lower alkyl, lower alkoxy and NRR′;-   R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower    hydroxyalkyl, lower cycloalkyl or is heterocycloalkyl optionally    substituted with hydroxy or alkoxy;-   R² is hydrogen, CN, lower alkyl or heterocycloalkyl;-   R and R′ are each independently hydrogen or lower alkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, or its corresponding enantiomer and/or optical isomer    and/or stereoisomer thereof.

The following compounds are encompassed by formula IA:

-   6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-Methyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine;-   6-(2-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine;-   6-(3-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine;-   6-(4-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine;-   2-Methyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-Methyl-6-p-tolylethynyl-pyrazolo[1,5-a]pyrimidine;-   6-(4-Chloro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(2-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(3-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(4-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(4-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-m-tolylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(3-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-p-tolylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(4-chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine;-   5-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-pyridin-2-ylamine;-   2-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-pyrimidin-5-ylethynyl-pyrazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(3,4-difluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;-   6-Phenylethynyl-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine;-   4-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-phenylamine;-   2-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-propan-2-ol;-   2-tert-Butyl-6-(5-fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine;-   6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile;-   3-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-phenylamine;-   2-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-phenylamine;-   2-tert-Butyl-6-(2,5-difluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine;    and-   2-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine.

In another embodiment, the invention provides compounds of formula IB,wherein X is C—R¹, Y is N and Z is CH,

wherein

-   R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2    nitrogen atoms, optionally substituted by 1 to 3 groups, selected    from halogen, lower alkyl, lower alkoxy and NRR′;-   R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower    hydroxyalkyl, lower cycloalkyl or heterocycloalkyl optionally    substituted with hydroxy or alkoxy;-   R and R′ are each independently hydrogen or lower alkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, or its corresponding enantiomer and/or optical isomer    and/or stereoisomer thereof.

The following compounds are encompassed by formula IB:

-   6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine;-   2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine and-   2-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol.

In another embodiment, the invention provides compounds of formula I,wherein X is C—R¹ and Y and Z are N.

wherein

-   R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2    nitrogen atoms, optionally substituted by 1 to 3 groups, selected    from halogen, lower alkyl, lower alkoxy and NRR′;-   R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower    hydroxyalkyl, lower cycloalkyl or heterocycloalkyl optionally    substituted with hydroxy or alkoxy;-   R and R′ are each independently hydrogen or lower alkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, or its corresponding enantiomer and/or optical isomer    and/or stereoisomer thereof.

The following compounds are encompassed by formula IC:

-   6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(2,5-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(3-fluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(3,4-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-Morpholin-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   2-Morpholin-4-yl-6-m-tolylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(3-Fluoro-phenylethynyl)-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine;-   6-(3-Chloro-phenylethynyl)-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine;    and-   6-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine.

A further embodiment, the invention provides compounds of formula I,wherein X is C—R¹, Y is C—R² and Z is CH.

wherein

-   R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2    nitrogen atoms, optionally substituted by 1 to 3 groups, selected    from halogen, lower alkyl, lower alkoxy and NRR′;-   R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy, lower    hydroxyalkyl, lower cycloalkyl or heterocycloalkyl optionally    substituted with hydroxy or alkoxy;-   R² is hydrogen, CN, lower alkyl or heterocycloalkyl;-   R and R′ are each independently hydrogen or lower alkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, or its corresponding enantiomer and/or optical isomer    and/or stereoisomer thereof.

The following compounds are encompassed by formula ID:

-   6-Phenylethynyl-pyrazolo[1,5-a]pyridine and-   2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridine.

In a further embodiment, the invention provides compounds of formula I,wherein X is N, Y is C—R² and Z is CH.

wherein

-   R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2    nitrogen atoms, optionally substituted by 1 to 3 groups, selected    from halogen, lower alkyl, lower alkoxy and NRR′;-   R² is hydrogen, CN, lower alkyl or heterocycloalkyl;-   R and R′ are each independently hydrogen or lower alkyl;    or a pharmaceutically acceptable acid addition salt, a racemic    mixture, or its corresponding enantiomer and/or optical isomer    and/or stereoisomer thereof.

The following compound is encompassed by formula IE:

-   6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridine.

The preparation of compounds of formula I of the present invention canbe carried out in sequential or convergent synthetic routes. Synthesesof the compounds of the invention are shown in the following schemes 1to 6. The skills required for carrying out the reaction and purificationof the resulting products are known to those skilled in the art. Thesubstituents and indices used in the following description of theprocesses have the significance given herein before.

The compounds of formula I can be manufactured by the methods givenbelow, by the methods given in the examples or by analogous methods.Appropriate reaction conditions for the individual reaction steps areknown to a person skilled in the art. The reaction sequence is notlimited to the one displayed in the schemes, however, depending on thestarting materials and their respective reactivity the sequence ofreaction steps can be freely altered. Starting materials are eithercommercially available or can be prepared by methods analogous to themethods given below, by methods described in references cited in thedescription or in the examples, or by methods known in the art.

The present compounds of formula I and their pharmaceutically acceptablesalts can be prepared by methods, known in the art, for example by theprocess variants described below, which process comprises

a) reacting a compound of formula 2

with a suitable aryl-acetylene of formula 3

to yield a compound of formula I

wherein the substituents are described above, orb) reacting a compound of formula 4

with a compound of formula 5

-   -   R⁴-hal 5        to yield a compound of formula I

wherein the substituents are described above and hal is halogen,selected from Cl, Br and I,c) reacting a compound of formula 6

with a suitable aryl-acetylene of formula 3

to yield a compound of formula I

wherein the substituents are described above, and,if desired, converting the compounds obtained into pharmaceuticallyacceptable acid addition salts.

The preparation of compounds of formula I is further described in moredetail in schemes 1 to 10 and in examples 1-51.

A 6-ethynyl-pyrazolo[1,5-a]pyrimidine of formula IA can be obtained bycondensation of an appropriately substituted 2-H-pyrazol-3-ylamine 7 andbromomalonaldehyde 8 with para-toluenesulfonic acid monohydrate in asolvent like n-butanol to yield the corresponding6-bromo-pyrazolo[1,5-a]pyrimidine derivative 9. Sonogashira coupling ofthe 6-bromo-pyrazolo[1,5-a]pyrimidine derivative 9 with an appropriatelysubstituted aryl-acetylene 3 yields the desired6-ethynyl-pyrazolo[1,5-a]pyrimidine of formula IA (scheme 1).

Alternatively, the intermediate 9 can be reacted in aSonogashira-coupling with trimethylsilyl acetylene 10 to give the6-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine derivative 11.Deprotection of the silyl-group with tetrabutylammonium fluoride (1.5mmol on silica gel) in a solvent like dichloromethane yields thecorresponding ethynyl derivative 12. Sonogashira coupling of 12 with anappropriately substituted aryl-halogenide yields the desired6-ethynyl-pyrazolo[1,5-a]pyrimidine of formula IA (scheme 2). Thisreaction sequence can alternatively be applied by coupling thetrimethylsilanyl derivative 11 with an appropriately substituted arylhalogenide under Sonogashira coupling conditions with simultaneousaddition of tetrabutylammonium fluoride which realizes the silyldeprotection in-situ.

A 6-ethynyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB can be obtainedby Sonogashira coupling of an aryl-acetylene 3 with2-amino-5-iodopyridine 13 to yield the corresponding5-ethynyl-pyridin-2-ylamine derivative 14. Reaction of 14 with a(1,1-dimethoxy-alkyl)-dimethyl-amine 15 in presence of an acidiccatalyst like trifluoroacetic acid and a solvent such as ethanol yieldsthe corresponding amidine 16, which is treated with hydroxylaminehydrochloride in a solvent such as i-PrOH:THF (5:1 v/v) to give thedesired N-hydroxyamidine 17. This compound is cyclized withtrifluoroacetic anhydride in a solvent such as THF to give the desired6-ethynyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB (scheme 3).

A 6-ethynyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula IC can beobtained similarly by reacting 2-amino-5-bromopyrimidine 18 with a(1,1-dimethoxy-alkyl)-dimethyl-amine 15 in presence of an acidiccatalyst like trifluoroacetic acid and a solvent such as ethanol to givethe corresponding amidine 19, which is treated with hydroxylaminehydrochloride in a solvent such as i-PrOH:THF (5:1 v/v) to give theN-hydroxyamidine 20. This compound is cyclized with trifluoroaceticanhydride in a solvent such as THF to give the desired6-ethynyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula IC (scheme 4).

A 6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID can be obtained bydecarboxylation of an appropriately substituted6-methoxy-pyrazolo[1,5-a]pyridine-3-carboxylic acid ester 22 withhydrobromic acid, yielding the corresponding pyrazolo[1,5-a]pyridin-6-olderivative 23, which is converted to the triflate derivative 25 usingtrifluoromethanesulfonic anhydride 24 and a base such as triethylaminein a solvent such as dichloromethane. Sonogashira coupling of 25 with anaryl-acetylene of formula 3 yields the desired6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID (scheme 5).

A 6-ethynyl-[1,2,3]triazolo[1,5-a]pyridine of formula IE can be obtainedby coupling of an appropriately substituted 5-halopyridine aldehyde orketone 26 with hydrazine in a solvent such as methanol, followed byoxidation with an oxidizing agent such as manganese dioxide yielding thecorresponding 6-bromo-[1,2,3]triazolo[1,5-a]pyridine derivative 27.Sonogashira coupling of 27 with an aryl-acetylene 3 yields the desired6-ethynyl-[1,2,3]triazolo[1,5-a]pyridine of formula IE (scheme 6).

A 6-ethynyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB can be obtainedby reaction of 2-amino-5-iodopyridine 13 with an appropriatelysubstituted acid chloride 28 in the presence of a base such as Et₃N in asolvent like dichloromethane to yield the correspondingN-(5-iodo-pyridin-2-yl)-amide 29. Reaction of 29 with Lawesson's reagentin a solvent like toluene yields the corresponding thioamide 30.Reacting 30 with hydroxylamine hydrochloride and a base such as Et₃N ina solvent like EtOH yields the corresponding hydroxyamidine 31, which istreated with p-TsCl and pyridine in a solvent like toluene to give thedesired 6-iodo-[1,2,4]triazolo[1,5-a]pyridine 32. Sonogashira couplingof 27 with an appropriately substituted aryl-acetylene 3 yields thedesired 6-ethynyl-[1,2,4]triazolo[1,5-a]pyridine of formula IB (scheme7).

A 6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID can be obtained byformation of 1-amino-3-bromo-pyridinium 2,4-dinitro-phenolate 35 from3-bromopyridine 33 and O-(2,4-dinitro-phenyl)-hydroxylamine 34 in asolvent like acetonitrile. Reacting the pyridinium derivative 35 with anappropriately substituted propynoic acid methyl ester 36 and a base suchas K₂CO₃ in a solvent like DMF yields the corresponding6-bromo-pyrazolo[1,5-a]pyridine-3-carboxylic acid ester 37, which isdecarboxylated with hydrobromic acid, yielding the corresponding6-bromo-pyrazolo[1,5-a]pyridine derivative 38. Sonogashira coupling of38 with an appropriately substituted aryl-acetylene 3 yields the desired6-ethynyl-pyrazolo[1,5-a]pyridine of formula ID (scheme 8).

A 6-ethynyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula IC can beobtained by condensation of an appropriately substituted1H-1,2,4-triazol-5-amine 39 with 2-bromomalonaldehyde 40 in AcOH to givethe corresponding 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine 21.Sonogashira coupling of 21 with an appropriately substitutedaryl-acetylene 3 yields the desired6-ethynyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula IC (scheme 9).

A 6-ethynyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula IC can also beobtained by condensation of an appropriately substituted1H-1,2,4-triazol-5-amine 39 with 2-bromomalonaldehyde 40 in AcOH to givethe corresponding 6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine 21.Sonogashira coupling of 21 with trimethylsilyl acetylene 10 yields thecorresponding 6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine41. Sonogashira coupling with in-situ desilylation of 41 and anappropriately substituted aryl-halogenide 5 yields the desired6-ethynyl-[1,2,4]triazolo[1,5-a]pyrimidine of formula IC (scheme 10).

Preferably, the compound of formula I as described herein as well as itspharmaceutically acceptable salt is used in the treatment or preventionof psychosis, epilepsy, schizophrenia, Alzheimer's disease, cognitivedisorders and memory deficits, chronic and acute pain, restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia, ischemia, Huntington'schorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS,eye injuries, retinopathy, idiopathic parkinsonism or parkinsonismcaused by medicaments, muscle spasms, convulsions, migraine, urinaryincontinence, gastrointestinal reflux disorder, liver damage or failurewhether drug or disease induced, Fragile-X syndrom, Down syndrom,autism, nicotine addiction, opiate addiction, anxiety, vomiting,dyskinesia, eating disorders, in particular bulimia or anorexia nervosa,and depressions, particularly for the treatment and prevention of acuteand/or chronic neurological disorders, anxiety, the treatment of chronicand acute pain, urinary incontinence and obesity.

The preferred indications are schizophrenia and cognitive disorders.

Present invention further relates to the use of a compound of formula Ias described herein, as well as its pharmaceutically acceptable salt,for the manufacture of a medicament, preferably for the treatment andprevention of the above-mentioned disorders.

Biological Assay and Data Intracellular Ca²⁺ Mobilization Assay

A monoclonal HEK-293 cell line stably transfected with a cDNA encodingfor the human mGlu5a receptor was generated; for the work with mGlu5Positive Allosteric Modulators (PAMs), a cell line with low receptorexpression levels and low constitutive receptor activity was selected toallow the differentiation of agonistic versus PAM activity. Cells werecultured according to standard protocols (Freshney, 2000) in Dulbecco'sModified Eagle Medium with high glucose supplemented with 1 mMglutamine, 10% (vol/vol) heat-inactivated bovine calf serum,Penicillin/Streptomycin, 50 μg/ml hygromycin and 15 μg/ml blasticidin(all cell culture reagents and antibiotics from Invitrogen, Basel,Switzerland).

About 24 hrs before an experiment, 5×10⁴ cells/well were seeded inpoly-D-lysine coated, black/clear-bottomed 96-well plates. The cellswere loaded with 2.5 μM Fluo-4AM in loading buffer (1×HBSS, 20 mM HEPES)for 1 hr at 37° C. and washed five times with loading buffer. The cellswere transferred into a Functional Drug Screening System 7000(Hamamatsu, Paris, France), and 11 half logarithmic serial dilutions oftest compound at 37° C. were added and the cells were incubated for10-30 min. with on-line recording of fluorescence. Following thispre-incubation step, the agonist L-glutamate was added to the cells at aconcentration corresponding to EC₂₀ (typically around 80 μM) withon-line recording of fluorescence; in order to account for day-to-dayvariations in the responsiveness of cells, the EC₂₀ of glutamate wasdetermined immediately ahead of each experiment by recording of a fulldose-response curve of glutamate.

Responses were measured as peak increase in fluorescence minus basal(i.e. fluorescence without addition of L-glutamate), normalized to themaximal stimulatory effect obtained with saturating concentrations ofL-glutamate. Graphs were plotted with the % maximal stimulatory usingXLfit, a curve fitting program that iteratively plots the data usingLevenburg Marquardt algorithm. The single site competition analysisequation used was y=A+((B−A)/(1+((x/C)D))), where y is the % maximalstimulatory effect, A is the minimum y, B is the maximum y, C is theEC₅₀, x is the log 10 of the concentration of the competing compound andD is the slope of the curve (the Hill Coefficient). From these curvesthe EC₅₀ (concentration at which half maximal stimulation was achieved),the Hill coefficient as well as the maximal response in % of the maximalstimulatory effect obtained with saturating concentrations ofL-glutamate were calculated.

Positive signals obtained during the pre-incubation with the PAM testcompounds (i.e. before application of an EC₂₀ concentration ofL-glutamate) were indicative of an agonistic activity, the absence ofsuch signals were demonstrating the lack of agonistic activities. Adepression of the signal observed after addition of the EC₂₀concentration of L-glutamate was indicative of an inhibitory activity ofthe test compound.

In the list of examples below are shown the corresponding results forcompounds which have EC₅₀<500 nM.

EC₅₀ (nM) Ex. Structure Name mGlu5PAM Eff. (%) 1

6-Phenylethynyl- pyrazolo[1,5-a]pyrimidine 70 116 2

2-Methyl-6-phenylethynyl- pyrazolo[1,5-a]pyrimidine 49 99 3

6-(2-Fluoro-phenylethynyl)- 2-methyl-pyrazolo[1,5- a]pyrimidine 47 81 4

6-(3-Fluoro-phenylethynyl)- 2-methyl-pyrazolo[1,5- a]pyrimidine 42 77 5

6-(4-Fluoro-phenylethynyl)- 2-methyl-pyrazolo[1,5- a]pyrimidine 78 74 6

2-Methyl-6-pyridin-4- ylethynyl-pyrazolo[1,5- a]pyrimidine 498 82 7

2-Methyl-6-p-tolylethynyl- pyrazolo[1,5-a]pyrimidine 132 73 8

6-(4-Chloro-phenylethynyl)- 2-methyl-pyrazolo[1,5- a]pyrimidine 148 69 9

2-tert-Butyl-6-phenylethynyl- pyrazolo[1,5-a]pyrimidine 5 75 10

2-tert-Butyl-6-(2-fluoro- phenylethynyl)-pyrazolo[1,5- a]pyrimidine 1980 11

2-tert-Butyl-6-(3-fluoro- phenylethynyl)-pyrazolo[1,5- a]pyrimidine 5 8612

2-tert-Butyl-6-(4-fluoro- phenylethynyl)-pyrazolo[1,5- a]pyrimidine 7 7513

2-tert-Butyl-6-pyridin-3- ylethynyl-pyrazolo[1,5- a]pyrimidine 33 88 14

2-tert-Butyl-6-pyridin-4- ylethynyl-pyrazolo[1,5- a]pyrimidine 4 37 15

2-tert-Butyl-6-(4-methoxy- phenylethynyl)-pyrazolo[1,5- a]pyrimidine 6853 16

2-tert-Butyl-6-m-tolylethynyl- pyrazolo[1,5-a]pyrimidine 100 50 17

2-tert-Butyl-6-(3-methoxy- phenylethynyl)-pyrazolo[1,5- a]pyrimidine 10441 18

2-Cyclobutyl-6- phenylethynyl-pyrazolo[1,5- a]pyrimidine 182 102 19

2-tert-Butyl-6-p-tolylethynyl- pyrazolo[1,5-a]pyrimidine 100 68 20

2-tert-Butyl-6-(4-chloro- phenylethynyl)-pyrazolo[1,5- a]pyrimidine 40089 21

2-tert-Butyl-6-(6-chloro- pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine 183 77 22

5-(2-tert-Butyl-pyrazolo[1,5- a]pyrimidin-6-ylethynyl)-pyridin-2-ylamine 255 98 23

2-tert-Butyl-6-(5-chloro- pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine 34 59 24

2-tert-Butyl-6-pyrimidin-5- ylethynyl-pyrazolo[1,5- a]pyrimidine 181 6825

2-tert-Butyl-6-(3,4-difluoro- phenylethynyl)-pyrazolo[1,5- a]pyrimidine45 93 26

6-Phenylethynyl-2- (tetrahydro-pyran-4-yl)- pyrazolo[1,5-a]pyrimidine472 124 27

4-(2-tert-Butyl-pyrazolo[1,5- a]pyrimidin-6-ylethynyl)- phenylamine 4199 28

2-(6-Phenylethynyl- pyrazolo[1,5-a]pyrimidin-2- yl)-propan-2-ol 152 5929

2-tert-Butyl-6-(5-fluoro- pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine 161 61 30

6-Phenylethynyl- pyrazolo[1,5-a]pyrimidine-3- carbonitrile 310 63 31

6-Phenylethynyl- [1,2,4]triazolo[1,5-a]pyridine 274 123 32

6-Phenylethynyl- [1,2,4]triazolo[1,5- a]pyrimidine 210 100 33

6-Phenylethynyl- pyrazolo[1,5-a]pyridine 136 88 34

6-Phenylethynyl- [1,2,3]triazolo[1,5-a]pyridine 50 77 35

3-(2-tert-Butyl-pyrazolo[1,5- a]pyrimidin-6-ylethynyl)- phenylamine 3769 36

2-(2-tert-Butyl-pyrazolo[1,5- a]pyrimidin-6-ylethynyl)- phenylamine 15588 37

2-tert-Butyl-6-(2,5-difluoro- phenylethynyl)-pyrazolo[1,5- a]pyrimidine39 65 38

2-Isopropyl-6-phenylethynyl- pyrazolo[1,5-a]pyrimidine 18 53 39

2-tert-Butyl-6-phenylethynyl- [1,2,4]triazolo[1,5-a]pyridine 30 54 40

2-Methyl-2-(6-phenylethynyl- [1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol 66 88 41

2-tert-Butyl-6-phenylethynyl- pyrazolo[1,5-a]pyridine 32 122 42

2-tert-Butyl-6-phenylethynyl- [1,2,4]triazolo[1,5- a]pyrimidine 9 73 43

2-tert-Butyl-6-(2,5-difluoro- phenylethynyl)- [1,2,4]triazolo[1,5-a]pyrimidine 14 37 44

2-tert-Butyl-6-(3-fluoro- phenylethynyl)- [1,2,4]triazolo[1,5-a]pyrimidine 9 85 45

2-tert-Butyl-6-(3,4-difluoro- phenylethynyl)- [1,2,4]triazolo[1,5-a]pyrimidine 28 54 46

2-tert-Butyl-6-(5-chloro- pyridin-3-ylethynyl)- [1,2,4]triazolo[1,5-a]pyrimidine 47 49 47

2-Morpholin-4-yl-6- phenylethynyl- [1,2,4]triazolo[1,5- a]pyrimidine 69119 48

2-Morpholin-4-yl-6-m- tolylethynyl- [1,2,4]triazolo[1,5- a]pyrimidine 5884 49

6-(3-Fluoro-phenylethynyl)- 2-morpholin-4-yl- [1,2,4]triazolo[1,5-a]pyrimidine 50 101 50

6-(3-Chloro-phenylethynyl)- 2-morpholin-4-yl- [1,2,4]triazolo[1,5-a]pyrimidine 39 88 51

6-Phenylethynyl-2-pyrrolidin- 1-yl-[1,2,4]triazolo[1,5- a]pyrimidine 56141

The present invention also provides pharmaceutical compositionscontaining compounds of the invention, for example, compounds of formulaI or pharmaceutically acceptable salts thereof and a pharmaceuticallyacceptable carrier. Such pharmaceutical compositions can be in the formof tablets, coated tablets, dragées, hard and soft gelatin capsules,solutions, emulsions or suspensions. The pharmaceutical compositionsalso can be in the form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compounds of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert, inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatin capsules. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatin capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula (I), but as arule are not necessary. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

The present invention also provides a method for the manufacture ofpharmaceutical compositions. Such process comprises bringing one or morecompounds of formula I and/or pharmaceutically acceptable acid additionsalts thereof and, if desired, one or more other therapeuticallyvaluable substances into a galenical administration form together withone or more therapeutically inert carriers.

As further mentioned earlier, the use of the compounds of formula (I)for the preparation of medicaments useful in the prevention and/or thetreatment of the above recited diseases is also an object of the presentinvention.

The dosage at which compounds of the present invention can beadministered can vary within wide limits and will, of course, be fittedto the individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01-20 mg/kg/day, with a dosage of 0.1-10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult humanbeing weighing 70 kg accordingly lies between 0.7-1400 mg per day,preferably between 7 and 700 mg per day.

Preparation of Pharmaceutical Compositions Comprising Compounds of theInvention:

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2Tablet weight 250

Experimental Section: Example 16-Phenylethynyl-pyrazolo[1,5-a]pyrimidine

Bis-(triphenylphosphine)-palladium(II)dichloride (27 mg, 0.04 mmol) wasdissolved in 1 ml of THF. 6-Bromo-pyrazolo[1,5-a]pyrimidine (150 mg,0.76 mmol) and phenylacetylene (130 μl, 1.21 mmol) were added at roomtemperature. Triethylamine (310 μl, 2.3 mmol), triphenylphosphine (6 mg,0.023 mmol) and copper(I) iodide (4 mg, 0.023 mmol) were added and themixture was stirred for 2 hours at 65° C. The reaction mixture wascooled and extracted with saturated NaHCO₃ solution and two times with asmall volume of dichloromethane. The crude product was purified by flashchromatography by directly loading the dichloromethane layers onto asilica gel column and eluting with heptane:ethyl acetate 100:0->50:50.The desired compound was obtained as a yellow solid (150 mg, 90% yield),MS: m/e=220.3 (M+H⁺).

Example 2 2-Methyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, white solid, MS: m/e=234.1 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and phenylacetylene.

Example 3 6-(2-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=252.1 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and1-ethynyl-2-fluoro-benzene.

Example 4 6-(3-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=252.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and1-ethynyl-3-fluoro-benzene.

Example 5 6-(4-Fluoro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=252.1 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and1-ethynyl-4-fluoro-benzene.

Example 6 2-Methyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, light brown solid, MS: m/e=235.1 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethynylpyridine.

Example 7 2-Methyl-6-p-tolylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, brown solid, MS: m/e=248.2 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 4-ethynyltoluene.

Example 8 6-(4-Chloro-phenylethynyl)-2-methyl-pyrazolo[1,5-a]pyrimidine

The title compound, brown solid, MS: m/e=268.1 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-methylpyrazolo[1,5-a]pyrimidine and 1-chloro-4-ethynylbenzene.

Example 9 2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine

3-tert-Butyl-1H-pyrazol-5-amine (9 g, 64.7 mmol) was dissolved in BuOH(100 ml). 2-Bromomalonaldehyde (9.76 g, 64.7 mmol) and p-TsOH*H₂O (615mg, 3.23 mmol) were added at room temperature. The mixture was stirredfor 16 hours at 100° C. The reaction mixture was evaporated to drynessand the residue was purified by flash chromatography on silica gel (120gr, 0% to 40% EtOAc in heptane) and crystallization with a small volumeof diisopropylether. The crystals were washed with diisopropylether anddried for 1 hour at 50° C. and <20 mbar. The desired compound wasobtained as a light yellow solid (9.5 g, 58% yield), MS: m/e=256.1/254.1(M+H⁺).

Step 2: 2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=276.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) andphenylacetylene.

Example 102-tert-Butyl-6-(2-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=294.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-2-fluoro-benzene.

Example 112-tert-Butyl-6-(3-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=294.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-3-fluoro-benzene.

Example 122-tert-Butyl-6-(4-fluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=294.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-4-fluoro-benzene.

Example 13 2-tert-Butyl-6-pyridin-3-ylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, white solid, MS: m/e=277.2 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and3-ethynylpyridine.

Example 14 2-tert-Butyl-6-pyridin-4-ylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, white solid, MS: m/e=277.1 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and4-ethynylpyridine.

Example 152-tert-Butyl-6-(4-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, yellow solid, MS: m/e=306.2 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-4-methoxybenzene.

Example 16 2-tert-Butyl-6-m-tolylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, yellow solid, MS: m/e=290.2 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-3-methylbenzene.

Example 172-tert-Butyl-6-(3-methoxy-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, yellow solid, MS: m/e=306.2 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-3-methoxybenzene.

Example 18 2-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-2-cyclobutyl-pyrazolo[1,5-a]pyrimidine

The title compound, yellow solid, MS: m/e=254.0/252.1 (M+H⁺), can beprepared in accordance with the general method of example 9, step 1 from5-cyclobutyl-1H-pyrazol-3-ylamine and 2-bromomalonaldehyde.

Step 2: 2-Cyclobutyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, light brown solid, MS: m/e=274.3 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-cyclobutyl-pyrazolo[1,5-a]pyrimidine (example 18, step 1) andphenylacetylene.

Example 19 2-tert-Butyl-6-p-tolylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=290.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-4-methylbenzene.

Example 202-tert-Butyl-6-(4-chloro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=310.1 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and1-ethynyl-4-chlorobenzene.

Example 212-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

Step 1: 2-tert-Butyl-6-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, brown solid, MS: m/e=272.3 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) andtrimethylsilylacetylene.

Step 2: 2-tert-Butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine

2-tert-Butyl-6-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine(example 21, step 1) (2.4 g, 8.85 mmol) was dissolved in dichloromethane(10 ml) and tetrabutylammoniumfluoride on silica gel (7.1 g, 10.6 mmol,1.5 mmol/g) was added at room temperature. The mixture was stirred for 2hours at room temperature and purified by flash chromatography bydirectly loading the mixture onto a 70 g silica gel column and elutingwith heptane:ethyl acetate 100:0->40:60. The desired compound wasobtained as a light yellow solid (1.45 g, 83% yield), MS: m/e=200.2(M+H⁺).

Step 3:2-tert-Butyl-6-(6-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=311.3 (M+H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 2-chloro-5-iodopyridine.

Example 225-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-pyridin-2-ylamine

The title compound, off white solid, MS: m/e=292.1 (M+H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 5-iodopyridin-2-amine.

Example 232-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=311.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 3-bromo-5-chloropyridine.

Example 242-tert-Butyl-6-pyrimidin-5-ylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=278.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 3-bromopyrimidine.

Example 252-tert-Butyl-6-(3,4-difluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=312.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 1,2-difluoro-4-iodobenzene.

Example 266-Phenylethynyl-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine

Step 1: 5-(Tetrahydro-pyran-4-yl)-2H-pyrazol-3-ylamine

The title compound can be prepared in accordance with the general methoddescribed in the patent application WO2008001070 (example 114).

Step 2: 6-Bromo-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine

The title compound, light brown solid, MS: m/e=284.0 (M+H⁺), can beprepared in accordance with the general method of example 9, step 1 from5-(tetrahydro-pyran-4-yl)-2H-pyrazol-3-ylamine (example 26, step 1) and2-bromomalonaldehyde.

Step 3:6-Phenylethynyl-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine

The title compound, grey solid, MS: m/e=304.1 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-(tetrahydro-pyran-4-yl)-pyrazolo[1,5-a]pyrimidine (example 26,step 2) and phenylacetylene.

Example 274-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-phenylamine

The title compound, brown solid, MS: m/e=291.2 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and4-ethynylaniline.

Example 28 2-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-propan-2-ol

Step 1: 6-Bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester

The title compound, brown solid, MS: m/e=256.0/254.1 (M+H⁺), can beprepared in accordance with the general method of example 9, step 1 frommethyl 5-amino-1H-pyrazole-3-carboxylate and 2-bromomalonaldehyde.

Step 2: 6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acidmethyl ester

The title compound, grey solid, MS: m/e=278.2 (M+H⁺), can be prepared inaccordance with the general method of example 1 from6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester(example 28, step 1) and phenylacetylene.

Step 3: 2-(6-Phenylethynyl-pyrazolo[1,5-a]pyrimidin-2-yl)-propan-2-ol

6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester(example 28, step 2) (60 mg, 0.22 mmol) was dissolved in 5 ml of THF andcooled to 0-5° C. Methylmagnesium chloride solution (150 μl, 0.45 mmol,3N in THF) was added dropwise at 0-5° C. The reaction mixture wasstirred for 30 minutes at 0-5° C. Water was added and the mixture wasextracted two times with ethyl acetate. The organic extracts were driedwith sodium sulfate, filtered and evaporated. The crude product waspurified by flash chromatography on silica gel (heptane:EtOAc100:0->70:30) and suspended in Et₂O. The desired compound was obtainedas a light brown solid (7 mg, 12% yield), MS: m/e=278.1 (M+H⁺).

Example 292-tert-Butyl-6-(5-fluoro-pyridin-3-ylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, light yellow solid, MS: m/e=295.3 (M+H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 3-bromo-5-fluorobenzene.

Example 30 6-Phenylethynyl-pyrazolo[1,5-a]pyrimidine-3-carbonitrile

The title compound, yellow solid, MS: m/e=245.2 (M++H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-pyrazolo(1,5-A)pyrimidine-3-carbonitrile and phenylacetylene.

Example 31 6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine

Step 1: 5-Phenylethynyl-pyridin-2-ylamine

The title compound, light yellow solid, MS: m/e=195.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from2-amino-5-iodopyridine and phenylacetylene.

Step 2: 6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine

The title compound, white solid, MS: m/e=220.3 (M++H⁺), can be preparedin accordance with the general method described in the patentapplication WO2007059257 (page 109, step A, B and C) starting from5-phenylethynyl-pyridin-2-ylamine (example 31, step 1).

Example 32 6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, white solid, MS: m/e=201.0/199.2 (M++H⁺), can beprepared in accordance with the general method described in the patentapplication WO2007059257 (page 109, step A, B and C) starting from2-amino-5-bromopyrimidine.

Step 2: 6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, light brown solid, MS: m/e=221.2 (M++H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-[1,2,4]triazolo[1,5-a]pyrimidine (example 32, step 1) andphenylacetylene.

Example 33 6-Phenylethynyl-pyrazolo[1,5-a]pyridine

Step 1: Pyrazolo[1,5-a]pyridin-6-ol

The title compound, white solid, MS: m/e=135.1 (M+H+), can be preparedin accordance with the general method described in EP1972628.

Step 2: Trifluoro-methanesulfonic acid pyrazolo[1,5-a]pyridin-6-yl ester

Pyrazolo[1,5-a]pyridin-6-ol (example 22, step 1) (200 mg, 1.49 mmol) wasdissolved in dichloromethane (10 ml) and triethylamine (200 μl, 1.49mmol) and trifluoromethanesulfonic anhydride (250 μl, 1.49 mmol) wereadded at 0-5° C. The mixture was stirred for 1 hour at room temperatureand extracted then with saturated NaHCO₃ solution and two times withdichloromethane. The organic layers were extracted with brine, driedover Na₂SO₄, filtered and evaporated to dryness. The desired compoundwas obtained as white solid (400 mg, quantitative), MS: m/e=267.0(M+H⁺).

Step 3: 6-Phenylethynyl-pyrazolo[1,5-a]pyridine

The title compound, light yellow solid, MS: m/e=219.2 (M+H⁺), can beprepared in accordance with the general method of example 1 fromtrifluoro-methanesulfonic acid pyrazolo[1,5-a]pyridin-6-yl ester(example 33, step 2) and phenylacetylene.

Example 34 6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridine

Step 1: 6-Bromo-[1,2,3]triazolo[1,5-a]pyridine

The title compound, light brown solid, MS: m/e=200.1/198.0 (M+H+), canbe prepared in accordance with the general method as described in B.Abarca et al./Tetrahedron 64 (2008) 3794-3801.

Step 2: 6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridine

The title compound, light brown solid, MS: m/e=220.3 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-[1,2,3]triazolo[1,5-a]pyridine (example 34, step 1) andphenylacetylene.

Example 353-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-phenylamine

The title compound, light yellow solid, MS: m/e=291.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and3-ethynylaniline.

Example 362-(2-tert-Butyl-pyrazolo[1,5-a]pyrimidin-6-ylethynyl)-phenylamine

The title compound, light yellow solid, MS: m/e=291.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyrimidine (example 9, step 1) and2-ethynylaniline.

Example 372-tert-Butyl-6-(2,5-difluoro-phenylethynyl)-pyrazolo[1,5-a]pyrimidine

The title compound, a white solid, MS: m/e=312.2 (M+H⁺), can be preparedin accordance with the general method of example 1 from2-tert-butyl-6-ethynyl-pyrazolo[1,5-a]pyrimidine (example 21, step 2)and 1,4-difluoro-2-iodobenzene.

Example 38 2-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-2-isopropyl-pyrazolo[1,5-a]pyrimidine

The title compound, a light yellow solid, MS: m/e=240.2/242.2 (M+H⁺),can be prepared in accordance with the general method of example 1, step1 from 5-isopropyl-2H-pyrazol-3-ylamine.

Step 2: 2-Isopropyl-6-phenylethynyl-pyrazolo[1,5-a]pyrimidine

The title compound, a brown solid, MS: m/e=245.2 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-isopropyl-pyrazolo[1,5-a]pyrimidine (example 38, step 1) andphenylacetylene.

Example 39 2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine

Step 1: N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-propionamide

5-Iodopyridin-2-amine (5 g, 22.7 mmol) was dissolved in 50 ml ofdichloromethane and Et₃N (6.3 ml, 45.5 mmol, 2 equiv.) was added at roomtemperature. The mixture was cooled to 0-5° C. and pivaloyl chloride(3.4 ml, 27.3 mmol, 1.2 equiv.) was added dropwise. The reaction mixturewas stirred for 1 hour at 0-5° C. Saturated NaHCO₃-solution was addedand the mixture was extracted with dichloromethane. The organic extractswere dried with sodium sulfate, filtered and evaporated to dryness. Thedesired N-(5-iodopyridin-2-yl)pivalamide (7.34 g, 99.8% yield) wasobtained as a brown oil, MS: m/e=305.0 (M+H⁺).

Step 2: N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide

N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-propionamide (example 39, step 1)(5.8 g, 19.1 mmol) was dissolved in 30 ml of toluene and Lawesson'sreagent (7.7 g, 19.1 mmol, 1 equiv.) was added at room temperature. Thereaction mixture was stirred for 48 hours at 110° C. The crude productwas purified by flash chromatography by directly loading the cooledtoluene reaction mixture onto a 300 g silica gel column and eluting withheptane:ethyl acetate 100:0->80:20. The desiredN-(5-iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide was obtained as ayellow oil (5.1 g, 75% yield), MS: m/e=321.0 (M+H⁺).

Step 3: N-Hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine

N-(5-Iodo-pyridin-2-yl)-2,2-dimethyl-thiopropionamide (example 39, step2) (5.1 g, 15.9 mmol) was dissolved in 50 ml of EtOH and Et₃N (2.9 ml,20.7 mmol, 1.3 equiv.) and hydroxylamine hydrochloride (1.3 g, 19.1mmol, 1.2 equiv.) were added at room temperature. The mixture wasstirred for 2 hours at room temperature. The suspension was diluted with100 ml of water and filtered. The crystals were washed with water anddried for 2 hours at 50° C. and <10 mbar. The desiredN-hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine (4.35 g,86% yield) was obtained as a white solid, MS: m/e=319.9 (M+H⁺).

Step 4: 2-tert-Butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine

N-Hydroxy-N′-(5-iodo-pyridin-2-yl)-2,2-dimethyl-propionamidine (example39, step 3) (2.8 g, 8.77 mmol) was suspended in 15 ml of toluene andpyridine (2.8 ml, 35.1 mmol, 4 equiv.). The mixture was cooled to 0-5°C. and p-toluenesulfonyl chloride (6.7 g, 35.1 mmol, 4 equiv.) wasadded. The reaction mixture was stirred for 1 hour at 0-5° C. and 4hours at room temperature. The reaction mixture was extracted withsaturated NaHCO₃ solution and two times with a small volume ofdichloromethane. The crude product was purified by flash chromatographyby directly loading the dichloromethane layers onto a 20 g silica gelcolumn and eluting with heptane:ethyl acetate 100:0->0:100. The desired2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (2 g, 76% yield) wasobtained as a light yellow oil, MS: m/e=302.1 (M+H⁺).

Step 5: 2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine

The title compound, a yellow solid, MS: m/e=276.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (example 39, step 4)and phenylacetylene.

Example 402-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol

Step 1: 3-Acetoxy-2,2-dimethyl-propionic acid

A solution of 3-hydroxy-2,2-dimethyl-propionic acid (1.5 g, 12.69 mmol)in 5 ml of acetyl chloride was heated at 80° C. under nitrogen for 2hours. The excess of acetyl chloride was evaporated under reducedpressure. The resulting residue was dissolved in dichloromethane andwashed with water. The organic layer was separated, dried and evaporatedto get the desired 3-acetoxy-2,2-dimethyl-propionic acid (1.65 g, 81%yield) as a colorless liquid.

Step 2: Acetic acid 2-chlorocarbonyl-2-methyl-propyl ester

To a solution of acetoxy-2,2-dimethyl-propionic acid (example 40,step 1) (2.2 g, 13.75 mmol) in CH₂Cl₂ (25 ml), were added oxalylchloride (2.62 ml, 27.50 mmol) and 2-4 drops of DMF and stirred at 25°C. for 3 hours. The solvent was evaporated and the resulting acetic acid2-chlorocarbonyl-2-methyl-propyl ester (2.4 g) was used directly in nextstep without purification.

Step 3: Acetic acid 2-(5-iodo-pyridin-2-ylcarbamoyl)-2-methyl-propylester

The title compound, a white solid, MS: m/e=363.2 (M+H⁺), can be preparedin accordance with the general method of example 39, step 1 from2-amino-5-iodopyridine and acetic acid 2-chlorocarbonyl-2-methyl-propylester (example 40, step 2).

Step 4: Acetic acid 2-(5-iodo-pyridin-2-ylthiocarbamoyl)-2-methyl-propylester

The title compound, MS: m/e=379.4 (M++H⁺), can be prepared in accordancewith the general method of example 39, step 2 from acetic acid2-(5-iodo-pyridin-2-ylcarbamoyl)-2-methyl-propyl ester (example 40, step3).

Step 5: Acetic acid2-[N-hydroxy-N′-(5-iodo-pyridin-2-yl)-carbamimidoyl]-2-methyl-propylester

The title compound, MS: m/e=378.0 (M++H⁺), can be prepared in accordancewith the general method of example 39, step 3 from acetic acid2-(5-iodo-pyridin-2-ylthiocarbamoyl)-2-methyl-propyl ester (example 40,step 4).

Step 6: Acetic acid2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propyl ester

The title compound, a white solid, MS: m/e=360.0 (M+H⁺), can be preparedin accordance with the general method of example 39, step 4 from aceticacid2-[N-hydroxy-N′-(5-iodo-pyridin-2-yl)-carbamimidoyl]-2-methyl-propylester (example 40, step 5).

Step 7:2-(6-Iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propan-1-ol

A solution of acetic acid2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propyl ester(example 40, step 6) (750 mg, 2.09 mmol) and K₂CO₃ (576 mg, 4.18 mmol, 2equiv.) in MeOH (8 ml) was stirred at 25° C. for 2 hours. The solventwas evaporated and the resulting crude product was purified by columnchromatography. The desired2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propan-1-ol (662mg, 91% yield) was obtained as a white solid, MS: m/e=318.0 (M+H⁺).

Step 8:2-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol

The title compound, a brown solid, MS: m/e=292.0 (M++H⁺), can beprepared in accordance with the general method of example 1 from2-(6-iodo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-2-methyl-propan-1-ol(example 40, step 7) and phenylacetylene.

Example 41 2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridine

Step 1: 1-Amino-3-bromo-pyridinium 2,4-dinitro-phenolate

To a solution of 3-bromopyridine (2.3 g, 15.0 mmol) in acetonitrile (4ml) was added 0-(2,4-dinitro-phenyl)-hydroxylamine (3.0 g, 15.0 mmol, 1equiv.) and the reaction mixture was stirred at 40° C. for 16 hours.Then the solvent was evaporated, the resulting residue was trituratedwith ether and dried to get the desired 1-amino-3-bromo-pyridinium2,4-dinitro-phenolate (4.5 g, 85% yield) as a brown solid.

Step 2: 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acidmethyl ester

To a solution of 1-amino-3-bromo-pyridinium 2,4-dinitro-phenolate(example 41, step 1) (1.98 g, 14.16 mmol) in DMF (20 ml) were added4,4-dimethyl-pent-2-ynoic acid methyl ester (CAS 20607-85-6) (5 g, 14.16mmol, 1 equiv.) and K₂CO₃ (3.9 g, 28.3 mmol, 2 equiv.) and stirred at25° C. while purging air. DMF was completely evaporated, the residuedissolved in ethyl acetate and washed with water (100 ml). The organicextract was dried with sodium sulfate, filtered and evaporated todryness. The resulting crude product along with the undesiredregioisomer 4-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylicacid methyl ester was purified by column chromatography. The desired6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid methylester (1.04 g, 24% yield) was obtained as a white solid, MS: m/e=312.2(M+H⁺).

Step 3: 6-Bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine

A solution of 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine-3-carboxylicacid methyl ester (example 41, step 2) (1.1 g, 3.53 mmol) in H₂SO₄ (5ml) and H₂O (5 ml) was heated at 80° C. for 36 hours. The reactionmixture was neutralized with 2N sodium hydroxide and extracted withethyl acetate (4×60 ml). The organic extracts were dried with sodiumsulfate, filtered and evaporated to dryness. The crude product waspurified by flash chromatography on silica gel (heptane:EtOAc95:5->90:10). The desired 6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine(370 mg, 38% yield) was obtained as a white solid, MS: m/e=254.2 (M+H⁺).

Step 4: 2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridine

The title compound, a white solid, MS: m/e=275.4 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-tert-butyl-pyrazolo[1,5-a]pyridine (example 41, step 3) andphenylacetylene.

Example 42 2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine

3-tert-Butyl-1H-1,2,4-triazol-5-amine (CAS 202403-45-0) (35%, 13 g, 32.5mmol) was dissolved in acetic acid (50 ml) and 2-bromomalonaldehyde(7.35 g, 48.7 mmol, 1.5 equiv.) was added. The reaction mixture wasstirred for 3 hours at 60° C. The reaction mixture was evaporated andneutralized with saturated NaHCO₃ solution 2N and extracted two timeswith dichloromethane. The organic extracts were dried with sodiumsulfate, filtered and evaporated to dryness. The crude product waspurified by flash chromatography on 70 g silica gel (heptane:EtOAc100:0->50:50). The desired6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (6.83 g, 83%yield) was obtained as a white solid, MS: m/e=255.0/257.1 (M+H⁺).

Step 2: 2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a yellow solid, MS: m/e=277.1 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42,step 1) and phenylacetylene.

Example 432-tert-Butyl-6-(2,5-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

Step 1:2-tert-Butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light yellow solid, MS: m/e=273.3 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42,step 1) and ethynyl-trimethyl-silane.

Step 2:2-tert-Butyl-6-(2,5-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

2-tert-Butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine(example 43, step 1) (100 mg, 0.37 mmol) was dissolved in DMF (1 ml).1,4-Difluoro-2-iodobenzene (176 mg, 0.73 mmol, 2 equiv.), Et₃N (150 μl,1.1 mmol, 3 equiv.), Bis-(triphenylphosphine)-palladium(II)dichloride(13 mg, 0.02 mmol, 0.05 equiv.), triphenylphosphine (3 mg, 0.011 mmol,0.03 equiv.) and copper(I)iodide (2 mg, 0.011, 0.03 equiv.) were addedunder nitrogen and the mixture was heated to 80° C. TBAF 1M in THF (440μl, 0.44 mmol, 1.2 equiv.) was added dropwise in 20 minutes at 80° C.The reaction mixture was stirred for 5 minutes at 80° C. The reactionmixture was evaporated and extracted with saturated NaHCO₃ solution andtwo times with a small volume of dichloromethane. The crude product waspurified by flash chromatography by directly loading the dichloromethanelayers onto a 20 g silica gel column and eluting with heptane:ethylacetate 100:0->50:50. The desired2-tert-butyl-6-(2,5-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine(73 mg, 64% yield) was obtained as a light yellow solid, MS: m/e=313.1(M+H⁺).

Example 442-tert-Butyl-6-(3-fluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light yellow solid, MS: m/e=295.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-tert-butyl-[1,2,4]triazolo[1,5-a]pyrimidine (example 42,step 1) and ethynyl-3-fluorobenzene.

Example 452-tert-Butyl-6-(3,4-difluoro-phenylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light yellow solid, MS: m/e=313.1 (M++H⁺), can beprepared in accordance with the general method of example 43, step 2from2-tert-butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine(example 43, step 1) and 3,4-difluoro-4-iodobenzene.

Example 462-tert-Butyl-6-(5-chloro-pyridin-3-ylethynyl)-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light yellow solid, MS: m/e=312.2/314.1 (M++H⁺),can be prepared in accordance with the general method of example 43,step 2 from2-tert-butyl-6-trimethylsilanylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine(example 43, step 1) and 3-chloro-5-iodopyridine.

Example 472-Morpholin-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light yellow solid, MS: m/e=284.2/286.1 (M+H⁺),can be prepared in accordance with the general method of example 42,step 1 from 5-morpholin-4-yl-2H-[1,2,4]triazol-3-ylamine (CAS51420-46-3) and 2-bromomalonaldehyde.

Step 2:2-Morpholin-4-yl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light brown solid, MS: m/e=306.1 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47,step 1) and phenylacetylene.

Example 482-Morpholin-4-yl-6-m-tolylethynyl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a brown solid, MS: m/e=320.2 (M+H⁺), can be preparedin accordance with the general method of example 1 from6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47,step 1) and ethynyl-3-methylbenzene.

Example 496-(3-Fluoro-phenylethynyl)-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light brown solid, MS: m/e=324.3 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47,step 1) and ethynyl-3-fluorobenzene.

Example 506-(3-Chloro-phenylethynyl)-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light brown solid, MS: m/e=340.0/342.1 (M+H⁺), canbe prepared in accordance with the general method of example 1 from6-bromo-2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 47,step 1) and ethynyl-3-chlorobenzene.

Example 516-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine

Step 1: 6-Bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light red solid, MS: m/e=268.1/270.1 (M+H⁺), canbe prepared in accordance with the general method of example 42, step 1from 5-pyrrolidin-1-yl-1H-[1,2,4]triazol-3-ylamine (CAS 154956-89-5) and2-bromomalonaldehyde.

Step 2:6-Phenylethynyl-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine

The title compound, a light brown solid, MS: m/e=290.2 (M+H⁺), can beprepared in accordance with the general method of example 1 from6-bromo-2-pyrrolidin-1-yl-[1,2,4]triazolo[1,5-a]pyrimidine (example 51,step 1) and phenylacetylene.

1. A compound of formula I

wherein X is N or C—R¹; Y is N or C—R²; Z is CH; R⁴ is a 6-memberedaromatic substituent containing 0, 1 or 2 nitrogen atoms, optionallysubstituted by 1 to 3 groups, selected from halogen, lower alkyl, loweralkoxy and NRR′; R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy,lower hydroxyalkyl, lower cycloalkyl or heterocycloalkyl optionallysubstituted with hydroxy or alkoxy; R² is hydrogen, CN, lower alkyl orheterocycloalkyl; and R and R′ are each independently hydrogen or loweralkyl; or a pharmaceutically acceptable salt or acid addition salt, aracemic mixture, an enantiomers, optical isomer or stereoisomer thereof.2. (canceled)
 3. (canceled)
 4. (canceled)
 5. (canceled)
 6. The compoundof claim 1, having formula IB,

wherein R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2nitrogen atoms, optionally substituted by 1 to 3 groups, selected fromhalogen, lower alkyl, lower alkoxy and NRR′; R¹ is hydrogen, loweralkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, lower cycloalkyl orheterocycloalkyl optionally substituted with hydroxy or alkoxy; and Rand R′ are each independently hydrogen or lower alkyl; or apharmaceutically acceptable acid addition salt, a racemic mixture, anenantiomers, optical isomer or stereoisomer thereof.
 7. The compoundclaim 6, selected from the group consisting of6-Phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine;2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine; and2-Methyl-2-(6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-propan-1-ol.8. (canceled)
 9. (canceled)
 10. The compound of claim 1 having formulaID,

wherein R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2nitrogen atoms, optionally substituted by 1 to 3 groups, selected fromhalogen, lower alkyl, lower alkoxy and NRR′; R¹ is hydrogen, loweralkyl, lower alkoxy, hydroxy, lower hydroxyalkyl, lower cycloalkyl orheterocycloalkyl optionally substituted with hydroxy or alkoxy; R² ishydrogen, CN, lower alkyl or heterocycloalkyl; and R and R′ are eachindependently hydrogen or lower alkyl; or a pharmaceutically acceptableacid addition salt, a racemic mixture, an enantiomers, optical isomer orstereoisomer thereof.
 11. The compound of claim 10, selected from thegroup consisting of 6-Phenylethynyl-pyrazolo[1,5-a]pyridine and2-tert-Butyl-6-phenylethynyl-pyrazolo[1,5-a]pyridine.
 12. The compoundof claim 1, having for formula IE,

wherein R⁴ is a 6-membered aromatic substituent containing 0, 1 or 2nitrogen atoms, optionally substituted by 1 to 3 groups, selected fromhalogen, lower alkyl, lower alkoxy and NRR′; R² is hydrogen, CN, loweralkyl or heterocycloalkyl; and R and R′ are each independently hydrogenor lower alkyl; or a pharmaceutically acceptable acid addition salt, aracemic mixture, an enantiomers, optical isomer or stereoisomer thereof.13. The compound of claim 12, which compound is6-Phenylethynyl-[1,2,3]triazolo[1,5-a]pyridine.
 14. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof formula I

wherein X is N or C—R¹; Y is N or C—R²; Z is CH; R⁴ is a 6-memberedaromatic substituent containing 0, 1 or 2 nitrogen atoms, optionallysubstituted by 1 to 3 groups, selected from halogen, lower alkyl, loweralkoxy and NRR′; R¹ is hydrogen, lower alkyl, lower alkoxy, hydroxy,lower hydroxyalkyl, lower cycloalkyl or heterocycloalkyl optionallysubstituted with hydroxy or alkoxy; R² is hydrogen, CN, lower alkyl orheterocycloalkyl; or R and R′ are each independently hydrogen or loweralkyl; or a pharmaceutically acceptable salt or acid addition salt, aracemic mixture, an enantiomers, optical isomer or stereoisomer thereofand a pharmaceutically acceptable carrier.
 15. The compound of claim 7,which compound is2-tert-Butyl-6-phenylethynyl-[1,2,4]triazolo[1,5-a]pyridine.